Design and Scale-Up of Diels-Alder Reactions for the Practical Synthesis of 5-Phenylbicyclo[2.2.2]oct-5-en-2-one

Several synthetic pathways towards racemic S-phenylbicyclo[2.2.2]oct-5-en-2-one 1 have been devised starting with a Diels-Alder reaction of (cyclohexa-1,5-dien-1-yloxy)trimethylsilane and alpha-acetoxyacrylonitrile, acrylonitrile, or alpha-chloroacrylonitrile. The first 'fit-for-purpose' route relied on alpha-acetoxyacrylonitrile as a dienophile and rapidly delivered kilogram amounts of 1. Process safety data then triggered the development of a scalable Diels-Alder reaction using alpha-chloroacrylonitrile as the dienophile. This practical and volume-efficient route delivered 1 in a 44% yield in six chemical steps with two isolated intermediates. Notably, neither chromatography nor distillation was required for the multikilogram synthesis of 1.